EP2190434B1 - Purin derivatives for use in the treatment of fap-related diseases - Google Patents

Purin derivatives for use in the treatment of fap-related diseases Download PDF

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Publication number
EP2190434B1
EP2190434B1 EP08787268.5A EP08787268A EP2190434B1 EP 2190434 B1 EP2190434 B1 EP 2190434B1 EP 08787268 A EP08787268 A EP 08787268A EP 2190434 B1 EP2190434 B1 EP 2190434B1
Authority
EP
European Patent Office
Prior art keywords
methyl
xanthine
amino
butyn
piperidin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Revoked
Application number
EP08787268.5A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP2190434A2 (en
Inventor
Frank Himmelsbach
Michael Mark
Mohammad Tadayyon
Leo Thomas
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Priority to EP19169300.1A priority Critical patent/EP3542801A1/en
Priority to EP08787268.5A priority patent/EP2190434B1/en
Publication of EP2190434A2 publication Critical patent/EP2190434A2/en
Application granted granted Critical
Publication of EP2190434B1 publication Critical patent/EP2190434B1/en
Revoked legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to use of a compound selected from
  • the present invention further relates to a compound selected from:
  • the specification describes the use of substances that have inhibitory capabilities, for the treatment of all kinds of pathological conditions.
  • Fibroblast Activation Protein also known as seprase, belongs to the family of serine proteases.
  • FAP like the enzyme DPP IV (dipeptidylpeptidase IV), for example, belongs to the enzymes that cleave a didpeptide from an existing protein or peptide with the general formula X-Pro-XAA.
  • DPP IV dipeptidylpeptidase IV
  • FAP is a transmembrane protein consisting of 760 amino acids. FAP exhibits a high homology with DPP IV and also forms heterodimers with this protein. Unlike DPP IV, the expression and activity of FAP is very limited. Thus, FAP is not expressed in normal adult tissues. FAP is induced in activated fibroblasts after trauma or injury to the tissue.
  • FAP is also expressed in tumour stroma tissue of all kinds of human epithelial tumours and in malignant cells of various bone and soft tissue sarcomas. These include, inter alia, more than 90% of breast, non-small-cell lung and colorectal carcinomas.
  • FAP is preferably found here in fibroblasts that occur close to newly forming or formed blood vessels and form a specific cellular compartment between the tumour capillary endothelium and the actual malignant epithelial cells and clusters of cells.
  • FAP-positive fibroblasts are found both in primary carcinomas and in metastasising carcinomas.
  • the expression profile of FAP suggests that FAP plays a part in tumour invasion into healthy tissue and in tumour formation and metastasis.
  • FAP inhibitors i.e.
  • FAP inhibitors can preferably be used to treat tumours of epithelial origin such as breast tumours, non-small-cell lung carcinomas, colorectal carcinomas and soft tissue carcinomas. FAP inhibitors are also indicated in all kinds of metastasising tumours such as melanomas, for example.
  • FAP inhibitors are also indicated in other hyperproliferative diseases. These include, inter alia, cardiac hypertrophy, cirrhoses and fibromatoses.
  • FAP inhibitors may also be used as valuable therapeutic agents for treating rheumatic spectrum diseases such as e.g. arthritis or osteoarthritis and neurotraumatic disorders. FAP inhibitors are also indicated for treating wound healing disorders and acne and proliferative skin complaints such as psoriasis, for example. Additionally, FAP inhibitors are indicated for treating pain of all origins and migraine.
  • R1 are pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyrimidin-2-ylmethyl, pyrimidin-4-ylmethyl, quinolin-2-ylmethyl, quinolin-3-ylmethyl, quinolin-4-ylmethyl, quinolin-5-ylmethyl, quinolin-6-ylmethyl, quinolin-7-ylmethyl, quinolin-8-ylmethyl, (2-oxo-1,2-dihydro-quinolin-6-yl)methyl, isoquinolin-1-ylmethyl, isoquinolin-3-ylmethyl, isoquinolin-4-ylmethyl, isoquinolin-8-ylmethyl, quinazolin-2-ylmethyl, quinazolin-4-ylmethyl, quinazolin-6-ylmethyl, quinazolin-7-ylmethyl, (4-oxo-3,4-dihydro-quinazolin-2-yl
  • R2 are methyl, carboxymethyl, methoxycarbonylmethyl, ethyloxycarbonylmethyl, cyclopropyl and phenyl, particularly methyl, carboxymethyl and phenyl.
  • R3 are 2-buten-1-yl, 3-methyl-2-buten-1-yl, 2-butyn-1-yl, benzyl, 2-chlorobenzyl, 2-bromobenzyl or 2-cyanobenzyl, particularly 3-methyl-2-buten-1-yl, 2-butyn-1-yl or benzyl.
  • R4 are piperazino, homopiperazino, 3-(R)-amino-piperidin-1-yl, 3-(S)-amino-piperidin-1-yl, (2-amino-ethyl)-methylamino, ((R)-2-amino-propyl)-methylamino or ((S)-2-amino-propyl)-methylamino.
  • the purine derivatives of general formulae (I) to (IV) can be prepared using methods known from the literature.
  • the purine derivatives of general formula (I) can be prepared for example as described in WO 2002/068420 , WO 2004/018468 , WO 2004/041820 , WO 2005/051950 , WO 2005/082906 , WO 2005/085246 , WO 2006/027204 and WO 2006/029769 .
  • the purine derivatives of general formula (II) can be prepared for example as described in WO 2004/050658 , WO 2004/111051 , WO 2005/058901 , WO 2005/097798 and WO 2005/110999 .
  • the purine derivatives of general formulae (III) and (IV) can be prepared for example as described in WO 2006/068163 and WO 2007/071738 .
  • Particularly preferred purine derivatives are the following compounds, the tautomers, enantiomers and the therapeutically effective salts thereof:
  • the FAP source used is a homogenised preparation of CD8huFAP cells and this is diluted with buffer in the ratio 1: 100.
  • the substrate used for the reaction is H-AlaPro_7-amido-4-trifluoromethylcoumarin (AlaPro-AFC) made by Bachem (Prod. No I-1680).
  • the test substances are diluted in DMSO (dimethylsulphoxide) and buffer and pipetted into a 96-well plate. 70 uL of the enzyme and 20 uL of the substrate are added thereto. The plate is incubated for one hour at ambient temperature, then the fluorescence is measured using a Wallac Victor 1420 Multilabel Counter at an excitation wavelength of 405 nm and an emission wavelength of 535 nm. The results were calculated by comparing the fluorescence in the presence of the test substance with the fluorescence of the control. The basal fluorescence was deducted.
  • the compounds according to the specification have an FAP inhibition of >50% at a concentration of 100 ⁇ M, for example.
  • the compounds according to the specification have an FAP inhibition of >50% at a concentration of 3 ⁇ M.
  • the compounds according to the specification are generally used for warm-blooded vertebrates, particularly humans, in doses of 0.001-100 mg/kg of body weight, preferably 0.1-15 mg/kg, 1 to 4 times per day.
  • the compounds, optionally combined with another active substance are formulated with one or more conventional inert carriers and/or diluents, e.g.
  • the pharmaceutical preparation is designed in accordance with the desired method of administration (oral, intravenous, parenteral, etc), the preferred formulation being an oral preparation.
  • compositions according to the specification containing the above- mentioned purine derivatives are thus prepared by the skilled man using permitted formulation excipients by methods as described in the prior art.
  • excipients are diluents, binders, carriers, fillers, lubricants, flow agents, crystallisation retardants, disintegrants, solubilisers, colourings, pH regulators, surfactants and emulsifiers.
  • Suitable diluents include cellulose powder, calcium hydrogen phosphate, erythritol, (low-substituted) hydroxypropylcellulose, mannitol, pregelatinised starch or xylitol.
  • Suitable binders include copolymers of vinylpyrrolidone with other vinyl derivatives (copovidone), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC) polyvinylpyrrolidone (povidone), pregelatinised starch, or low-substituted hydroxypropylcellulose.
  • Suitable lubricants include talc, polyethyleneglycol, calcium behenate, calcium stearate, hydrogenated castor oil or magnesium stearate.
  • Suitable disintegrants include maize starch or crospovidone.
  • an FAP inhibitor is combined with a (permitted) active substance commonly used for the ailment in question, e.g. with an active substance having anti-hyperproliferative properties or with an active substance that can be used for the treatment of hyperproliferative diseases (e.g. cancers).
  • Such a combined treatment may be given as a free combination of the active substances or in the form of a fixed combination, for example in a tablet or capsule.
  • Pharmaceutical formulations of the combination partner needed for this may either be obtained commercially as pharmaceutical compositions or may be formulated by the skilled man using conventional methods.
  • the active substances which may be obtained commercially as pharmaceutical compositions are described in numerous places in the prior art, for example in the list of drugs that appears annually, the "Rote Liste ®" of the Federal Association of the Pharmaceutical Industry, or in the annually updated compilation of manufacturers' information on prescription drugs known as the "Physicians' Desk Reference".
  • the anti-cancer treatment defined here may be used as a sole therapy or may comprise, in addition to the compound according to the specification, conventional surgery, radiation therapy or chemotherapy.
  • Such chemotherapy may comprise one or more of the following categories of chemotherapeutic and/or targeted antitumour agents:
  • bleomycin retinoids such as all-trans retinoic acid (ATRA), DNA methyltransferase inhibitors such as decitabine (Docagen) or 5-azacytidine, alanosine, cytokines such as interleukin-2, interferons such as interferon-alpha2 or interferon-gamma, death receptor agonists such as TRAIL, DR4/5 agonistic antibodies, FasL and TNF-R agonists (e.g. TRAIL receptor agonists such as mapatumumab or lexatumumab), as well as HDAC inhibitors such as SAHA.
  • ATRA all-trans retinoic acid
  • Docagen DNA methyltransferase inhibitors
  • Docagen DNA methyltransferase inhibitors
  • 5-azacytidine alanosine
  • cytokines such as interleukin-2
  • interferons such as interferon-alpha2 or interferon-gamma

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
EP08787268.5A 2007-08-17 2008-08-15 Purin derivatives for use in the treatment of fap-related diseases Revoked EP2190434B1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP19169300.1A EP3542801A1 (en) 2007-08-17 2008-08-15 Purin derivatives for use in the treatment of fap-related diseases
EP08787268.5A EP2190434B1 (en) 2007-08-17 2008-08-15 Purin derivatives for use in the treatment of fap-related diseases

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP07114494 2007-08-17
EP08787268.5A EP2190434B1 (en) 2007-08-17 2008-08-15 Purin derivatives for use in the treatment of fap-related diseases
PCT/EP2008/060740 WO2009024542A2 (en) 2007-08-17 2008-08-15 Purin derivatives for use in the treatment of fab-related diseases

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP19169300.1A Division EP3542801A1 (en) 2007-08-17 2008-08-15 Purin derivatives for use in the treatment of fap-related diseases

Publications (2)

Publication Number Publication Date
EP2190434A2 EP2190434A2 (en) 2010-06-02
EP2190434B1 true EP2190434B1 (en) 2019-04-17

Family

ID=40378740

Family Applications (2)

Application Number Title Priority Date Filing Date
EP08787268.5A Revoked EP2190434B1 (en) 2007-08-17 2008-08-15 Purin derivatives for use in the treatment of fap-related diseases
EP19169300.1A Withdrawn EP3542801A1 (en) 2007-08-17 2008-08-15 Purin derivatives for use in the treatment of fap-related diseases

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP19169300.1A Withdrawn EP3542801A1 (en) 2007-08-17 2008-08-15 Purin derivatives for use in the treatment of fap-related diseases

Country Status (14)

Country Link
US (2) US20110112069A1 (ko)
EP (2) EP2190434B1 (ko)
JP (1) JP5769966B2 (ko)
KR (1) KR101610005B1 (ko)
CN (1) CN101784278A (ko)
AU (1) AU2008290582B2 (ko)
BR (1) BRPI0815405A2 (ko)
CA (1) CA2696579C (ko)
ES (1) ES2733348T3 (ko)
MX (1) MX2010001821A (ko)
NZ (1) NZ600126A (ko)
RU (1) RU2569749C2 (ko)
WO (1) WO2009024542A2 (ko)
ZA (1) ZA201000075B (ko)

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US20160136180A1 (en) 2016-05-19
AU2008290582B2 (en) 2014-08-14
RU2569749C2 (ru) 2015-11-27
RU2010109545A (ru) 2011-09-27
CA2696579A1 (en) 2009-02-26
ZA201000075B (en) 2010-09-29
ES2733348T3 (es) 2019-11-28
WO2009024542A3 (en) 2009-05-22
NZ600126A (en) 2013-12-20
AU2008290582A1 (en) 2009-02-26
BRPI0815405A2 (pt) 2015-02-03
CN101784278A (zh) 2010-07-21
US20110112069A1 (en) 2011-05-12
EP3542801A1 (en) 2019-09-25
KR101610005B1 (ko) 2016-04-08
CA2696579C (en) 2017-01-24
JP2010536820A (ja) 2010-12-02
WO2009024542A2 (en) 2009-02-26
KR20100055423A (ko) 2010-05-26

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